This proposal requests support for the investigation of new approaches in the treatment of propionic acidemia and for the improvement of those determined previously to be beneficial. We will study methods of monitoring positive protein balance in patients with propionic acidemia. In addition, we will develop a simpler, direct method for assessing biotin-responsiveness in these patients, substantiating these results by examining responsiveness in fibroblast cultures representing the various genetic complementation groups. We will formulate and evaluate other potentially useful modes of therapy derived from our studies of biotin and related metabolism in perfused liver of hepatocyte cultures of biotin-deficient rats. We will clinically evaluate the therapeutic usefulness of high-dose oral glycine administration and cholesterol restriction in the dietary management of patients with propionyl CoA carboxylase deficiency. We plan also to evaluate the efficacy of treatment, retrospectively and potentially, in an inbred population with multiple affected members demonstrating marked clinical heterogeneity.